Early electrical stimulation promotes functional recovery after volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the inherent regenerative capacity of skeletal muscle, causing persistent functional deficits with no routinely effective therapies. Electrical stimulation (ES) is a promising regenerative cue, but its sustained delivery during the acute post-injury window has been limited by the electrochemical performance of available stimulation electrodes and by the repeated anesthesia that needle-electrode delivery requires for each session, which constrains daily dosing in rodent models. Here, we report a fully implantable bioelectronic system in which nanoporous platinum (NanoPt) modification of multistrand stainless-steel electrodes provides the high charge storage and injection capacities required for safe, repeatable stimulation in a rat tibialis anterior VML model. Electrochemical characterization confirmed that the porous NanoPt surface lowered impedance, increased charge storage and injection capacities, and remained stable over 48 h of continuous stimulation in muscle-mimicking phantom tissue. The electrode platform enabled daily therapeutic stimulation and electromyographic recording in awake, freely moving animals, removing the per-session anesthesia that percutaneous needle-electrode delivery requires during the early dosing window. Animals receiving ES during the acute post-injury period (10 sessions over days 0-14) showed sustained functional improvement, reaching 90% of baseline torque at 8 weeks compared to 71% in unstimulated controls, reflecting enhanced remodeling of the injured muscle rather than synergistic compensation. Histological analysis revealed early increases in vascularization, pro-regenerative macrophages, and satellite cells that accompanied, and temporally preceded, the functional gains. By coupling a biomaterial-enabled electrode platform to a defined stimulation regimen, this work identifies the acute post-injury period as a therapeutically actionable window and provides a basis for combining bioelectronic interventions with engineered scaffolds and other regenerative biomaterials for traumatic muscle loss. STATEMENT OF SIGNIFICANCE: Severe traumatic muscle injuries cause permanent weakness because lost muscle is not regrown and no biomaterial-based therapy reliably reverses the deficit. Electrical stimulation is a promising regenerative cue, but the electrode materials and procedures required for daily stimulation during the brief post-injury healing window have remained elusive. Here, nanoporous platinum-modified electrodes provide the electrochemical stability and charge-handling capacity needed to deliver sustained daily stimulation in awake animals, without the per-session anesthesia required by needle-electrode approaches, in a rat model of volumetric muscle loss. Two weeks of immediate post-injury stimulation restored near-normal limb strength while enhancing vascularization, pro-regenerative macrophages, and satellite-cell activity. This biomaterial-enabled bioelectronic platform identifies the acute post-injury period as a therapeutic window and a basis for combining electrical stimulation with regenerative biomaterials.